Novel Intervention for Colitis

结肠炎的新型干预措施

基本信息

批准号：
7218881
负责人：
MICHAEL PETER VITEK
金额：
$ 27.93万
依托单位：
COGNOSCI, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-05 至 2008-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7218881
关键词：
Abdominal Pain Acute Adrenal Cortex Hormones Adverse effects Affect Allergic American Amino Acids Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Arginine Automobile Driving Blood Brain Brain Diseases Cells Chronic Citrobacter rodentium Clinical Colitis Collaborations Colon Condition Crohn&apos s disease Data Dextran Sulfate Diabetes Mellitus Diarrhea Diet Disease Disorder by Site Dose Enzymes Epithelial Cells Equilibrium Family Fistula Gastrointestinal Diseases Generations Genus Cola Grant Human Immunology Immunosuppressive Agents In Vitro Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Intervention Intestines Laboratories Link Malignant Neoplasms Measures Mediator of activation protein Metabolism Modality Modeling Monoclonal Antibodies Morbidity - disease rate Mucositis Multiple Sclerosis Mus Muscle Cramp Natural Immunity Nitric Oxide Nitric Oxide Synthase Obstruction One-Step dentin bonding system Onset of illness Ornithine Decarboxylase Outcome Outcome Measure Pancreatitis Pathway interactions Patients Peptides Perforation Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Play Polyamines Production Proteins Publishing Quality of life Regulation Risk Role Score Sepsis Severities Severity of illness Sodium Sodium Dextran Sulfate Spinal Cord Symptoms Systemic infection Therapeutic Tissues Treatment Protocols Ulcerative Colitis Universities Wild Type Mouse Work analog arginase base bone loss clinically relevant cytokine gastrointestinal human disease improved in vivo infliximab inhibitor/antagonist innovation interest macrophage mimetics mouse model novel novel therapeutics receptor binding research study response small molecule symposium trait

项目摘要

DESCRIPTION (provided by applicant): Novel Intervention for Colitis The scope of the current proposal is to determine whether administration of an apoE mimetic peptide, COG112, improves clinical, histological and inflammatory outcomes in clinically relevant paradigms of colitis. Specifically, we will employ the acute Citrobacter rodentium (C. rodentium) model, an acute Dextran Sulfate Sodium (DSS) model and a chronic DSS model of colitis. We will also define whether there is a dose-dependent response to treatment with COG112 in these models of human disease. This course of experiments has the potential to represent a novel therapeutic strategy for a difficult gastrointestinal disease in which adequate treatment strategies do not currently exist. Specific Aim 1: Using a C. rodentium-infectious model of acute colitis, measure the response to treatment with different doses of COG112 using clinical outcome measures, histological outcome measures and measures of a panel of representative inflammatory mediators. Specific Aim 2: Using a DSS model of acute colitis, measure the response to treatment with different doses of COG112 using clinical outcome measures, histological outcome measures and measures of a panel of representative inflammatory mediators. Specific Aim 3: Using a DSS model of chronic colitis, measure the response to treatment with different doses of COG112 using clinical outcome measures, histological outcome measures and measures of a panel of representative inflammatory mediators. Novel Intervention for Colitis: Inflammatory Bowel Disease (IBD), more commonly known as Crohn's disease and ulcerative colitis, affects approximately 1 million Americans with inflammation of the intestines, abdominal pain, cramping and diarrhea. These symptoms vary in severity, but are often debilitating for patients to the extent that they greatly alter their quality of life. We have found that clinical and histological scores of IBD are less when the levels of small molecules known as polyamines are increased. To increase polyamine levels, one needs to increase the amount of arginine, an amino acid derived from our diets, that is converted to polyamines through the action of the arginase/ornithine decarboxylase pathway. We have found a novel drug, COG112, can stimulate this arginase activity. Thus, mouse models of colitis treated with COG112 should have less disease than their untreated counterparts. So we propose to directly measure whether COG112 will exacerbate or ameliorate colitis in mouse models.

描述（由申请人提供）：结肠炎的新干预措施当前提案的范围是确定apoE模拟肽COG112的施用是否改善临床相关结肠炎范例中的临床、组织学和炎症结果。具体来说，我们将采用急性柠檬酸杆菌（C. rodentium）模型、急性葡聚糖硫酸钠（DSS）模型和慢性DSS结肠炎模型。我们还将确定在这些人类疾病模型中 COG112 治疗是否存在剂量依赖性反应。这个实验过程有可能为目前尚不存在适当治疗策略的疑难胃肠道疾病提供一种新的治疗策略。具体目标 1：使用急性结肠炎的啮齿类动物感染模型，使用临床结果测量、组织学结果测量和一组代表性炎症介质的测量来测量对不同剂量 COG112 治疗的反应。具体目标 2：使用急性结肠炎的 DSS 模型，使用临床结果测量、组织学结果测量和一组代表性炎症介质的测量来测量对不同剂量 COG112 治疗的反应。具体目标 3：使用慢性结肠炎的 DSS 模型，使用临床结果测量、组织学结果测量和一组代表性炎症介质的测量来测量对不同剂量 COG112 治疗的反应。结肠炎的新型干预措施：炎症性肠病 (IBD)，通常称为克罗恩病和溃疡性结肠炎，影响大约 100 万美国人，伴有肠道炎症、腹痛、痉挛和腹泻。这些症状的严重程度各不相同，但通常会使患者变得虚弱，从而极大地改变他们的生活质量。我们发现，当称为多胺的小分子水平增加时，IBD 的临床和组织学评分会降低。为了增加多胺水平，需要增加精氨酸的量，精氨酸是一种来自我们饮食的氨基酸，通过精氨酸酶/鸟氨酸脱羧酶途径的作用转化为多胺。我们发现了一种新药 COG112 可以刺激这种精氨酸酶活性。因此，用 COG112 治疗的小鼠结肠炎模型应该比未治疗的小鼠模型患有更少的疾病。因此，我们建议直接测量 COG112 是否会加剧或改善小鼠模型中的结肠炎。